The present invention relates to novel derivatives 1-diphenylmethyl piperazine, their process of preparation as well as their use as medicaments.
The compounds according to the present invention correspond to the general formula I ##STR2## in which:
R.sub.1 and R.sub.2, equal or different, represent a hydrogen atom, a halogen, a lower alkyl radical, a hydroxy radical, an alkoxy radical, an alkyl carboxylate radical, an aryl radical or substituted aryl radical,
n can have the values 2 to 4,
X, Y, Z, and W, equal or different, represent a nitrogen atom or a carbon atom linked to a hydrogen atom, a halogen or to another alkyl, aryl, carboxylalkyl, carboxy, hydroxyl, sulfonyl and alkylsulfonyl radical.
These novel derivatives, and their pharmaceutically acceptable salts, show very good antihistaminic activity.
In the scientific literature there have already been known, for a long time, derivatives of diphenylmethyl piperazine with antihistaminic activity, like chlorciclicine (Baltzly and al., J. Org. Chem., 14, 775, 1949); meclicine (Bull. Soc. Chimie Belge., 60, 282, 1951). cetyrizine (EP 58146). However, in general, the usual antihistamines show side effects of stimulation or of depression of the central nervous system. On the other hand, we have discovered that derivatives of the general formula I, and their pharmaceutically acceptable salts, do not show side effects on the central nervous system.
The novel deritives of general formula I may be prepared, according to the invention, according to any one of the following methods:
Method A--By reaction of a compound of general formula ##STR3## in which R.sub.1, R.sub.2, and n have the previously mentioned meanings, and A represents a halogen atom, or a good "starting group" selected from among tosyloxy or mesyloxy, with a compound of general formula III ##STR4## in which X, Y, Z, and W have the previously mentioned meanings.
The reaction is conducted in the presence of a suitable solvent, for example dimethylsulfoxide, dimethylformanide, alcohol, hydrocarbons, aromatic or not, ethers, such as dioxan or diphenyl ether, or mixtures of these solvents. This reaction is avantageously performed in the presence of a base such as hydroxides, carbonates or bicarbonates of alkali metals, or of a mixture of these bases. It is possible to employ also hydrides of alkali metals. The most suitable temperatures vary between room temperature and the reflux temperature of the solvent, and the reaction time is comprised between 1 hour and 24 hours.
Method B--By reaction of a compound of general formula IIa, in which A represents a --NH.sub.2 radical, with 2.5-dimethoxytetrahydrofuran.
The reaction is conducted in the presence of a suitable solvent, for example acetic acid, a water, alcohols, ketones or mixtures of these solvents. The most suitable temperatures vary between room temperature and the reflux temperature of the solvent, and the reaction time is comprised of some minutes and 24 hours.
Method C--By reaction of a compound of general formula IV ##STR5## in which R.sub.1, R.sub.2 have the previously mentioned meanings, with a compound of general formula V ##STR6## where X, Y, Z, W and n have the previously mentioned meanings and B represents a halogen atom, or a good "starting group" selected from among tosyloxy or mesyloxy.
The reaction is carried out in the presence of a suitable solvent, for example dimethylsulfoxide, dimethylformamide, alcohols, hydrocarbons, aromatic or not, ethers, such as dioxan or diphenyl ether, or mixtures of these solvents. This reaction is advantageously conducted in the presence of a base such as hydroxide, carbonates or bicarbonates of alkali metals, or of a mixture of these bases. The most suitable temperatures vary between room temperature and the reflux temperature of the solvent, and the reaction time is comprised between 1 hour and 24 hours.
In the following examples, the preparation of the novel derivatives according to the invention is indicated. The following examples, given purely by way of illustration, must not however, in any case, be taken as limiting the scope of the invention.